Synonyms: Cereblon modulator 1 | Compound 1 [WO2019006299A1] [1] | compound 16 [PMID: 33591756]
Compound class:
Synthetic organic
Comment: CC-90009 is a clinical stage cereblon E3 ligase modulating drug (CELMoD), that targets the G1 to S phase transition 1 (GSPT1, a.k.a. eRF3A) protein for degradation via the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex [2]. Binding of CC-90009 to cereblon alters its conformation, and promotes a change in substrate selectivity away from the transcription factors IKZF1/3 and towards to GSPT1. CC-90009-induced depletion of GSPT1 promotes apoptosis of acute myeloid leukemia (AML) cells via activation of the GCN1/GCN2/ATF4 pathway [3-4].
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References |
1. Buchholz TJ, Carmichael J, Carrancio S, Fan J, Gupta R, Lu G, Macbeth M, Pace E, Pierce D, Pourdehnad M et al.. (2019)
Compositions and methods of use of 2-(4-chlorophenyl)-n-((2-(2,6-doxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl) -2,2-difluoroacetamide. Patent number: WO2019006299A1. Assignee: Celgene Corporation. Priority date: 30/06/2017. Publication date: 03/01/2019. |
2. Hansen JD, Correa M, Alexander M, Nagy M, Huang D, Sapienza J, Lu G, LeBrun LA, Cathers BE, Zhang W et al.. (2021)
CC-90009: A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia. J Med Chem, 64 (4): 1835-1843. [PMID:33591756] |
3. Lopez-Girona A, Lu G, Rychak E, Mendy D, Lu C-C, Rappley I, Fontanillo C, Cathers BE, Daniel TO, Hansen J. (2019)
CC-90009, a Novel Cereblon E3 Ligase Modulator, Targets GSPT1 for Degradation to Induce Potent Tumoricidal Activity Against Acute Myeloid Leukemia (AML). Blood, 134: 2703. DOI: 10.1182/blood-2019-127892 |
4. Surka C, Jin L, Mbong N, Lu CC, Jang IS, Rychak E, Mendy D, Clayton T, Tindall E, Hsu C et al.. (2021)
CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells. Blood, 137 (5): 661-677. DOI: 10.1182/blood.2020008676 [PMID:33197925] |